At present, the definitive diagnosis of Alzheimer's disease (AD) is based on the pathologic confirmation of amyloid plaques and neurofibrillary tangles in the cerebral cortex. Over many years, our research efforts have been directed toward the development of non-invasive methods for the in vivo measurement of amyloid plaques. Toward this goal, our group recently collaborated with researchers in Uppsala, Sweden, to perform the first human positron emission tomography (PET) studies of a new amyloidbinding radiotracer, named PIB (Pittsburgh Compound B). These first human studies demonstrated high PIB retention in AD subjects (n=9) in brain areas known to have high amyloid levels in AD (relative to controls, n=5). The next step in our efforts is to establish the validity of the PIB PET methodology and to determine a valid and simple method for potential clinical use. The central goal of this application is to validate the PIB PET methodology and identify a simple PIB measure of amyloid-binding that is feasible for routine use. Toward this goal, PIB PET studies will be acquired in 3 subject groups: mild-to-moderate AD dementia (n=12), mild cognitive impairment (n=12), and elderly controls (n=12). PIB localization will be related to measures of brain glucose metabolism (using [18F]FDG), which has been extensively used as a metabolic index of AD. Validation will include acquisition of [15O]water PET data to exclude the influence of variations in blood flow on PIB binding. Structural MRI data will be acquired in all subjects to provide anatomical guidance for the PET data analyses. Our first aim is to identify an optimal fully-quantitative (arterial blood) PIB PET method. The second aim is to choose a valid and simple (no blood sampling) PIB PET method based upon the fully-quantitative data and an iterative evaluation of observed and computer-simulated PIB data. The simple method will allow rapid generation of robust image maps of amyloid binding throughout brain. The final aim is to relate anatomically standardized maps of amyloid binding to maps of cerebral metabolism. This research will provide important groundwork to support the use of the PIB measure of amyloid binding in early and pre-clinical diagnosis of AD and potentially accelerate the development and evaluation of important new therapies for dementia.